Diuretic aerosols and methods of making and using them

ABSTRACT

Described herein are diuretic condensation aerosols and methods of making and using them. Kits for delivering a condensation aerosol are also described. The diuretic aerosols typically comprise diuretic condensation aerosol particles that comprise a diuretic compound. In some variations the diuretic compound is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928, and BG 9719. Methods of treating edema using the described aerosols are also provided. In general, the methods typically comprise the step of administering a therapeutically effective amount of diuretic condensation aerosol to a person with edema. The diuretic condensation aerosol may be administered in a single inhalation, or may be administered in more than one inhalation. Methods of forming a diuretic condensation aerosol are also described. The methods typically comprise the steps of providing a diuretic composition, vaporizing the composition to form a vapor, and then condensing the diuretic composition vapor.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/429,123 entitled, “Delivery of a Diuretic through anInhalation Route” filed on Nov. 26, 2002, the entirety of which ishereby incorporated by reference.

BACKGROUND

[0002] Edema is a localized or general swelling caused by the build-upof fluid within body tissues. It most commonly occurs in the feet andlegs, where it also is referred to as peripheral edema. However, excessfluid can occur anywhere in the subcutaneous tissue or lungs. Thisexcess fluid may be the result of any number of causes. For example, itmay be the result of poor blood circulation, lymphatic system failure,disease of the heart or kidneys, reduction in the amount of bloodprotein (e.g., which may occur as a result of cirrhosis), chronicnephritis, malnutrition, or toxemia of pregnancy (preeclampsia). Someother causes of edema are use of birth control pills, premenstrualsyndrome, sunburn, and an imbalance of sodium and potassium. Localizededema may also result from injury or infection.

[0003] Diuretics are most typically used to treate edema. Some diureticsare used to treat Meniere's disease and other types of vertigo whereexcessive fluid pressure builds up within the inner ear. Some diureticsare used to treat glaucoma, where excessive fluid pressure builds upwithin the eyeball. Similarly, some diuretics are used to treatpulmonary edema, where fluid accumulates in the lung tissue. Diureticsmay also be used to treat high blood pressure (i.e., hypertension),overdosage of certain drugs, and cystic fibrosis.

[0004] There are a number of compositions commercially available asdiuretics. These include ethacrynic acid, bumetanide, furosemide,muzolimine, spironolactone, torsemide, triamterene, and tripamide. Thesediuretics are most commonly delivered as an oral dosage form (e.g. as apill, capsule, or tablet), or delivered intravenously. Disadvantages oforal dosage forms include a delay in the onset of activity and loss ofdrug therapeutic effect due to hepatic first-pass metabolism.Intravenous delivery, while typically more effective than oral delivery(particularly for loop diuretics), is often painful and inconvenient.Currently, intravenous delivery is the only option available forexacerbations of congestive heart failure. It would be desirable toprovide other dosage forms and routes of administration with improvedproperties.

SUMMARY

[0005] Described herein are diuretic condensation aerosols and methodsof making and using them. Kits for delivering a condensation aerosol arealso described. The diuretic aerosols described herein typicallycomprise diuretic condensation aerosol particles, where the particlescomprises a diuretic selected from the group consisting of bumetanide,ethacrynic acid, furosemide, muzolimine, spironolactorie, torisemide,triamterene, tripamide, BG 9928, and BG 9719. In some variations thediuretic compound is bumetanide.

[0006] In some variations, the aerosol comprises at least 50% by weightof diuretic condensation particles. In other variations the aerosolcomprises at least 75% or 95% by weight of the diuretic condensationparticles. Similarly, in some variations, the aerosol is substantiallyfree of thermal degradation products, and in some variations, thediuretic condensation aerosol has a NMAD in the range of 1-3 μm.

[0007] The kit for delivering a diuretic condensation aerosol typicallycomprises a composition comprising a diuretic compound, and a device forforming a diuretic aerosol. The device for forming a diuretic aerosoltypically comprises an element configured to heat the composition toform a vapor, an element allowing the vapor to condense to form acondensation aerosol, and an element permitting a user to inhale thecondensation aerosol. The composition may further comprise apharmaceutically acceptable excipient, and the device my furthercomprise features such as breath-actuation or lock-out elements.

[0008] Methods of treating edema using the aerosols described herein arealso provided. In general, the method comprises the step ofadministering a therapeutically effective amount of a diureticcondensation aerosol to a person with edema. The edema may be caused orbe associated with any number of maladies. For example, the edema may bethe result of congestive heart failure, cirrhosis of the liver, poorblood circulation, lymphatic system failure, chronic nephritis,malnutrition, toxemia of pregnancy (preeclampsia), use of birth controlpills, premenstrual syndrome, sunburn, hypertension, overdosage ofcertain drugs, Meniere's disease, glaucoma, cystic fibrosis, and animbalance of sodium and potassium. Localized edema may also result frominjury or infection.

[0009] In some variations, the method for treating edema comprising thestep of administering a therapeutically effective amount of a diureticaerosol to a person with edema, wherein the diuretic aerosol comprises adiuretic compound and has a MMAD in the range of about 1-3 μm, andwherein a peak plasma level of at least 30 ng/mL of the diureticcompound is achieved within 10 minutes of administration. In somevariations, the method comprises the steps of obtaining a weightmeasurement of the person with edema prior to the step of administeringa therapeutically effective amount of a diuretic aerosol, and using thatweight measurement to assess whether to administer a therapeuticallyeffective amount of a diuretic aerosol.

[0010] In some variations, the described condensation aerosol has a MMADin the range of about 1-3 μm. In some variations, the condensationaerosol comprises a diuretic selected from the group consisting ofbumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone,torsemide, triamterene, tripamide, BG 9928, and BG 9719. In somevariations the diuretic compound is bumetanide. In other variations, thediuretic achieves a C_(max) within a certain time period after theaerosol is administered. For example, in some variations, the diureticachieves a C_(max) in 10 minutes or less after the aerosol isadministered. The diuretic condensation aerosol may be administered in asingle inhalation, or may be administered in more than one inhalation.

[0011] Methods of treating congestive heart failure using the aerosolsdescribed herein are also provided. In general, the method comprises thestep of administering a therapeutically effective amount of a loopdiuretic condensation aerosol to a person with congestive heart failure.This method may be particularly useful in treating those symptomsassociated with congestive heart failure exacerbations.

[0012] In some variations, the method for treating congestive heartfailure exacerbation comprising the step of administering atherapeutically effective amount of a loop diuretic aerosol to a personwith symptoms of congestive heart failure exacerbation, wherein the loopdiuretic aerosol comprises a loop diuretic compound and has a MMAD inthe range of about 1-3 μm, and wherein a peak plasma level of at least30 ng/mL of the loop diuretic compound is achieved within 10 minutes ofadministration. In other variations, the loop diuretic achieves aC_(max) within a certain time period after the aerosol is administered.For example, in some variations, the loop diuretic achieves a C_(max) in10 minutes or less after the aerosol is administered. The loop diureticcondensation aerosol may be administered in a single inhalation, or maybe administered in more than one inhalation.

[0013] Methods of forming a diuretic condensation aerosol are alsodescribed. The methods of forming a diuretic condensation aerosoltypically comprise the steps of providing a diuretic composition,vaporizing the diuretic composition, and condensing the diureticcomposition. The step of vaporizing the diuretic composition typicallycomprises the step of heating the composition to form a vapor.

[0014] The composition typically comprises a diuretic selected from thegroup consisting of bumetanide, ethacrynic acid, furosemide, muzolimine,spironolactone, torsemide, triamterene, and tripamide, BG 9928, and BG9719. In some variations the diuretic compound is bumetanide. Thediuretic composition may also comprise a pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 is an illustration of an exemplary device that may be usedto form and administer the aerosols described herein.

[0016]FIGS. 2A and 2B are illustrations of other exemplary devices thatmay be used to form and administer the aerosols described herein.

[0017]FIGS. 3A and 3B illustrate solid supports suitable for use withthe devices and methods described herein.

[0018]FIG. 4 is a plot depicting the effects of film thickness onaerosol purity for bumetanide.

DETAILED DESCRIPTION

[0019] Definitions

[0020] As defined herein, the following terms shall have the followingmeanings when reference is made to them throughout the specification.

[0021] “Condensation aerosol” refers to an aerosol that has been formedby the vaporization and subsequent cooling of the vapor, such that thevapor condenses to form particles.

[0022] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0023] “Substantially free of thermal degradation products” means thatthe aerosol is at least 50% free of thermal degradation products.

[0024] “Therapeutically effective amount” means the amount required toachieve a therapeutic effect. The therapeutic effect could be anytherapeutic effect ranging from prevention, symptom amelioration,symptom treatment, to disease termination or cure.

[0025] “Thermal degradation product” means any byproduct, which resultsfrom heating the diuretic composition and is not responsible forproducing a therapeutic effect.

[0026] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0027] Diuretic Compositions

[0028] The diuretic compositions described herein typically comprise atleast one diuretic compound. The diuretic compositions may compriseother compounds as well. For example, the diuretic composition maycomprise a mixture of diuretic compounds, a mixture of a diureticcompound and a pharmaceutically acceptable excipient, or a mixture of adiuretic compound with other compounds having useful or desirableproperties. The diuretic composition may comprise a pure diureticcompound as well.

[0029] Any suitable diuretic compound may be used. In general, we havefound that suitable diuretics have properties that make them acceptablecandidates for use with the devices and methods herein described. Forexample, the diuretic compound is typically one that is, or can be madeto be, vaporizable.

[0030] Classes of diuretics suitable for use with the described methodsand devices include the carbonic anhydrase inhibitors, osmoticdiuretics, loop diuretics, thiazide and thiazide-like diuretics,potassium sparing diuretics, and aldosterone antagonists. Exemplarydiuretic compounds within these classes include bumetanide, ethacrynicacid, furosemide, muzolimine, spironolactone, torsemide, triamterene,tripamide, BG 9928 (Bicyclo [2,2,2]octane-1-propanoic acid,4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8yl)-(9CI)), andBG 9719 (1H-Purine-2,6-dione,3,7-dihydro-8-(3-oxatricyclo[3,2,1,02,4]oct-6-yl)-1,3-dipropyl-[ 1S-(1α,2β,4β,5α,6β)], and pharmaceutically acceptable analogs andequivalents thereof. A table providing chemical structures and somephysical properties for a few of these illustrative compounds isprovided below. TABLE 1 Suitable Diuretic Compounds

Bumetanide Ethacrynic Acid C₁₇H₂₀N₂O₅S C₁₃H₁₂Cl₂O₄ Mol. Wt.: 364.4 Mol.Wt.: 303.1 Log P: 2.61 Log P: 3.05 CLogP: 3.37219 CLogP: 3.44499

Muzolimine Tripamide C₁₁H₁₁Cl₂N₃O C₁₆H₂₀ClN₃O₃S Mol. Wt.: 272.1 Mol.Wt.: 369.9 Log P: 2.18 Log P: 1.72 CLogP: 1.328 CLogP: 2.47501

Triamterene Spironolactone C₁₂H₁₁N₇ C₂₄H₃₂O₄S Mol. Wt.: 253.3 Mol. Wt.:416.6 Log P: 2.11 Log P: 2.90 CLogP: 1.60761 CLogP: 2.249

BG-9928 BG-9719 C₂₂H₃₂N₄O₄ CVT-124 Mol. Wt.: 416.5 C₁₈H₂₄N₄O₃ Log P:3.33 Mol. Wt.: 344.4 CLogP: 4.6225 Log P: 1.43 CLogP: 2.5535

[0031] Typically, the diuretic compound is in its ester or free acidform. However, it is not without possibility that the diuretic compoundwill be vaporizable from its salt form. Indeed, a variety ofpharmaceutically acceptable salts are suitable for aerosolization.Illustrative salts include, without limitation, the following: sodium,potassium, or other alkali metal salts, and ammonium or substitutedammonium salts. Salt forms of diuretics can be obtained from theircorresponding free acid using well known methods in the art.

[0032] Suitable pharmaceutically acceptable excipients may be volatileor nonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with the diuretic. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within these classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0033] Solid Support

[0034] Typically, the diuretic composition is coated on a solid support,and then the solid support is heated to vaporize the diureticcomposition. The support may be of any geometry and be of a variety ofdifferent sizes. It is often desirable that the solid support provide alarge surface to volume ratio (e.g., greater than 100 per meter) and alarge surface to mass ratio (e.g., greater than 1 cm² per gram).

[0035] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 perriveter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0036] A number of different materials may be used to construct thesolid supports. Classes of such materials include, without limitation,metals, inorganic materials, carbonaceous materials, and polymers.Illustrative materials within these classes are aluminum, silver, iron,gold, stainless steel, copper and tungsten; silica, glass, silicon andalumina; graphite, porous carbons, carbon yams and carbon felts,ceramics; and polytetrafluoroethylene. In one variation, the solidsupport is stainless steel. Combinations of materials and coatedvariants of materials may be used as well.

[0037] When it is desirable to use aluminum as a solid support, aluminumfoil is a suitable material. Examples of silica, alumina and siliconbased materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yams and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0038] Typically it is desirable that the solid support have relativelyfew, or substantially no, surface irregularities. Although a variety ofsupports may be used, supports that have an impermeable surface, or animpermeable surface coating, are typically desirable. Illustrativeexamples of such supports include metal foils, smooth metal surfaces,nonporous ceramics, and the like.

[0039] The diuretic composition is typically coated on the solid supportin the form of a film. The film may be coated on the solid support usingany suitable method. The method suitable for coating is often dependentupon the physical properties of the diuretic compound and the desiredfilm thickness. One exemplary method of coating a diuretic compositionon a solid support is by preparing a solution of diuretic compound(alone or in combination with other desirable compounds) in a suitablesolvent, applying the solution to the exterior surface of the solidsupport, and then removing the solvent (e.g., via evaporation, etc.)thereby leaving a film on the support surface.

[0040] Common solvents include methanol, dichloromethane, methyl ethylketone, diethyl ether, 3:1 chloroform:methanol mixture, 1:1dichloromethane: methyl ethyl ketone mixture, dimethylformamide, anddeionized water. In some instances (e.g., when triamterene is used), itis desirable to use a solvent such as formic acid. Sonication may alsobe used as necessary to dissolve the diuretic compound.

[0041] The diuretic composition may also be coated on the solid supportby dipping the support into a diuretic composition solution, or byspraying, brushing or otherwise applying the solution to the support.Alternatively, a melt of the drug can be prepared and applied to thesupport. For drugs that are liquids at room temperature, thickeningagents can be mixed with the drug to permit application of a solid drugfilm.

[0042] Formation of Diuretic Condensation Aerosols

[0043] Any suitable method may be used to form the condensation aerosolsdescribed herein. One such method involves the heating of a diureticcomposition to form a vapor, followed by cooling of the vapor so that itforms an aerosol (i.e., a condensation aerosol). Exemplary methods ofheating include the passage of current through an electrical resistanceelement, absorption of electromagnetic radiation (e.g., microwave orlaser light) and exothermic chemical reactions (e.g., exothermicsalvation, hydration of pyrophoric materials, and oxidation ofcombustible materials). Heating of the substrate by conductive heatingis also suitable. One exemplary heating source is described in U.S.patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, U.S. Ser. No. 60/472,697 filed May 21, 2003. Thedescription of the exemplary heating source diosclosed therein, ishereby incorporated by reference.

[0044] Heat sources or devices that contain a chemically reactivematerial, which undergoes an exothermic reaction upon actuation, e.g.,by a spark or heat element, such as a flashbulb type heater described inU.S. patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLYUNIT EMPLOYING SAME, are also suitable. In particular, heat sources thatgenerate heat by exothermic reaction, where the chemical “load” of thesource is consumed in a period of between 50-500 msec or less aregenerally suitable, assuming good thermal coupling between the heatsource and substrate.

[0045] In one method, the heating of the diuretic composition involvesheating a thin film of the composition having a thickness between about0.05 μm-20 μm to form a vapor. In yet other variations, the compositionhas a film thickness between about 0.5 μm-10 μm. Most typically, thefilm thickness vaporized is between 0.5 μm-5 μm.

[0046] In some variations, the diuretic condensation aerosol comprisesat least 5% by weight of diuretic condensation aerosol particles. Inother variations, the aerosol comprises at least 10%, 20%, 30%, 40%,50%, 60%, or 75% by weight of diuretic condensation aerosol particles.In still other variations, the aerosol comprises at least 95%, 99%, or99.5% by weight of diuretic condensation aerosol particles.

[0047] In some variations, the diuretic condensation aerosol particlescomprise less than 10% by weight of a thermal degradation product. Inother variations, the diuretic condensation aerosol particles compriseless than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a thermaldegradation product.

[0048] In some variations the diuretic condensation aerosol has a MMADin the range of about 1-3 μm. In some variations the geometric standarddeviation around the MMAD of the diuretic condensation aerosol particlesis less than 3.0. In other variations, the geometric standard deviationaround the MMAD of the diuretic condensation aerosol particles is lessthan 2.5, or less than 2.0.

[0049] The aerosol particles for administration can typically be formedusing any of the describe methods at a rate of greater than 10⁸inhalable particles per second. In some variations, the aerosolparticles for administration are formed at a rate of greater than 10⁹ or10¹⁰ inhalable particles per second. Similarly, with respect to aerosolformation (i.e., the mass of aerosolized particulate matter produced bya delivery device per unit time) the aerosol may be formed at a rategreater than 0.25 mg/second, grater than 0.5 mg/second, or greater than1 or 2 mg/second.

[0050] Delivery Device

[0051] The delivery devices described herein for administering adiuretic condensation aerosol typically comprise an element for heatingthe diuretic composition to form a vapor, an element allowing the vaporto cool, thereby forming a condensation aerosol, and an elementpermitting a user to inhale the aerosol. The delivery device may becombined with a composition comprising a diuretic compound in unit doseform for use as a Kit.

[0052] One suitable device is illustrated in FIG. 1. Delivery device 100has a proximal end 102 and a distal end 104, a solid support 106, apower source 108, and a mouthpiece 110. In this depiction, solid support106 also comprises a heating module. A diuretic composition is depositedon solid support 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element, etc.).

[0053] The diuretic composition vaporizes and condenses to form acondensation aerosol prior to reaching the mouthpiece 110 at theproximal end of the device 102. Air flow traveling from the devicedistal end 104 to the mouthpiece 1 10 carries the condensation aerosolto the mouthpiece 110, where it is inhaled by a user.

[0054] The devices described herein may additionally contain a varietyof components to facilitate aerosol delivery. For instance, the devicemay include any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation).Similarly, the device may include a component to provide feedback topatients on the rate and/or volume of inhalation, or a component toprevent excessive use (i.e., “lock-out” feature). In addition, thedevice may further include a component to prevent use by unauthorizedindividuals, and a component to record dosing histories. Thesecomponents may be used alone, or in combination with other components.

[0055] The element that allows cooling may be of any configuration. Forexample, it may be an inert passageway linking the heating means to theinhalation means. Similarly, the element permitting inhalation by a usermay be of any configuration. For example, it may be an exit portal thatforms a connection between the cooling element and the user'srespiratory system.

[0056] Other suitable devices for use with the aerosols described hereinare shown in FIGS. 2A and 2B. As shown in FIG. 2A, there is a device 200comprising an element for heating a diuretic composition to form avapor, an element allowing the vapor to cool, thereby forming acondensation aerosol, and an element permitting a user to inhale theaerosol. Device 200 also comprises a housing 202 with a tapered end 204for insertion into the mouth of a user. On the end opposite tapered end204, the housing has one or more openings, such as slots 206, for airintake when a user places the device in the mouth and of the figure. Atleast a portion of the solid support is coated on a surface 210 with afilm 212 of a diuretic composition.

[0057] Typically, the solid support 208 is heated to a temperaturesufficient to vaporize all or a portion of the film 212, so that thediuretic composition forms a vapor that becomes entrained in a stream ofair during inhalation. As noted above, heating of the solid support 208may be accomplished using, for example, an electrically-resistive wireembedded or inserted into the substrate and connected to a batterydisposed in the housing. The heating can be actuated, for example, witha button on the housing or via breath actuation, as is known in the art.

[0058]FIG. 2B shows another device that may be used to form and deliverthe aerosols described herein. The device, 214 comprises an element forheating a diuretic composition to form a vapor, an element allowing thevapor to cool, thereby forming a condensation aerosol, and an elementpermitting a user to inhale the aerosol. The device also comprises anupper external housing member 216 and a lower external housing member218 that fit together.

[0059] Shown in the depiction of FIG. 2B, the downstream end of eachhousing member is gently tapered for insertion into a user's mouth, asbest seen on upper housing member 216 at downstream end 220. Theupstream end of the upper and lower housing members are slotted, as seenbest in the figure in the upper housing member at 222, to provide forair intake when a user inhales. The upper and lower housing members whenfitted together define a chamber 224. Positioned within chamber 224 is asolid support 226, shown in a partial cut-away view.

[0060] As shown in FIG. 2B, the solid support shown there is of asubstantially cylindrical configuration having a slight taper. However,as described above the solid support may be of any desirableconfiguration. At least a portion of the solid support surface 228 iscoated with a diuretic composition film 230. Visible in the cutawayportion of the solid support is an interior region 232, which comprisesa substance suitable to generate heat. The substance may be, forexample, a solid chemical fuel, chemical reagents that mixexothermically, an electrically resistive wire, or the like. A powersupply source, in end piece 234.

[0061] The device may also include a gas-flow control valve disposedupstream of the solid support, for limiting gas-flow rate through thecondensation region. The gas-flow valve may, for example, include aninlet port communicating with the chamber, and a deformable flap adaptedto divert or restrict air flow away from the port increasingly, withincreasing pressure drop across the valve. Similarly, the gas-flow valvemay include an actuation switch. In this variation, the valve movementwould be in response to an air pressure differential across the valve,which for example, could function to close the switch. The gas-flowvalve may also include an orifice designed to limit airflow rate intothe chamber.

[0062] The device may also include a bypass valve communicating with thechamber downstream of the unit for offsetting the decrease in airflowproduced by the gas-flow control valve, as the user draws air into thechamber. In this way, the bypass valve could cooperate with thegas-control valve to control the flow through the condensation region ofthe chamber as well as the total amount of air being drawn through thedevice. Thus the total volumetric airflow through the device in thisvariation would be the sum of the volumetric airflow rate through thegas-control valve and the volumetric airflow rate through the bypassvalve.

[0063] The gas control valve could, for example, function to limit airdrawn into the device to a preselected level, e.g., 15 L/minute. In thisway, air flow for producing particles of a desired size may bepreselected and produced. For example, once this selected airflow levelis reached, additional air drawn into the device would create a pressuredrop across the bypass valve, which in turn would accommodate airflowthrough the bypass valve into the downstream end of the device adjacentthe user's mouth. Thus, the user senses a full breath being drawn in,with the two valves distributing the total airflow between desiredairflow rate and bypass airflow rate.

[0064] These valves may be used to control the gas velocity through thecondensation region of the chamber and hence to control the particlesize of the aerosol particles produced. Typically, the faster theairflow, the smaller the particles. Thus, to achieve smaller or largerparticles, the gas velocity through the condensation region of thechamber may be altered by modifying the gas-flow control valve toincrease or decrease the volumetric airflow rate. For example, toproduce condensation particles in the size range of about 1-3.5 μm MMAD,a chamber having substantially smooth-surfaced walls would have aselected gas-flow rate in the range of 4-50 L/minute.

[0065] Additionally, as will be appreciated by one of skill in the art,particle size may be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate, and/or the presence or absence ofstructures that produce turbulence within the chamber. Thus, for exampleto produce condensation particles in the size range 10-100 nm MMAD, thechamber may provide gas-flow barriers for creating air turbulence withinthe condensation chamber. These barriers are typically placed within afew thousands of an inch from the substrate surface. Particle size isdiscussed in more detail below.

[0066]FIGS. 3A and 3B provide exploded views of solid supports that maybe used in combination with the devices described herein. As shown inFIG. 3A, there is a solid support 300 having a diuretic compositioncoating 302 at least a portion of the upper surface 304. While thecoating 302 is shown on upper surface 304 in FIG. 3A, it should beunderstood that it need not be so. Indeed, the coating may be placed onany suitable surface, such as surfaces 306 and 308.

[0067]FIG. 3B provides a perspective, cut-away view of another solidsupport 310 that may be used with the methods and devices hereindescribed. As shown there, the solid support 310 comprises acylindrically-shaped substrate 312. This substrate may be formed from aheat-conductive material, for example. The exterior surface 314 ofsubstrate 312 is coated with a diuretic composition. As shown in thecut-away portion, there is a heating element 316 disposed in thesubstrate. The substrate can be hollow with a heating element insertedinto the hollow space or solid with a heating element incorporated intothe substrate.

[0068] The illustrative heating element shown in FIG. 3B is shown as anelectrical resistive wire that produces heat when a current flowsthrough it, but as noted above, a number of different heating methodsand corresponding devices are acceptable. For example, acceptable heatsources can supply heat to the solid support at rates that rapidlyachieve a temperature sufficient to completely vaporize the diureticcomposition from the support surface. For example, heat sources thatachieve a temperature of 200° C. to 500° C. within a period of 2seconds, although it should be appreciated that the temperature chosenwill be dependent upon the vaporization properties of the diureticcomposition.

[0069] Diuretic Composition Film Thickness

[0070] Typically, the diuretic composition film coated on the solidsupport has a thickness of between about 0.05-20 μm, and typically athickness between 0.1-15 μm. More typically, the thickness is betweenabout 0.2-10 μm; even more typically, the thickness is between about0.5-10 μm, and most typically, the thickness is between about 0.5-5 μm.The desirable film thickness for any given diuretic composition istypically determined by an iterative process in which the desired yieldand purity of the condensation aerosol composition are selected orknown.

[0071] For example, if the purity of the particles is less than thatwhich is desired, or if the percent yield is less than that which isdesired, the thickness of the drug film is adjusted to a thicknessdifferent from the initial film thickness. The purity and yield are thendetermined at the adjusted film thickness, and this process is repeateduntil the desired purity and yield are achieved. After selection of anappropriate film thickness, the area of substrate required to provide atherapeutically effective dose, is determined.

[0072] An example of how film thickness affects purity is depicted inFIG. 4 for the diuretic compound bumetanide.

[0073] Solid Support Surface Area

[0074] As noted above, the surface area of the solid support is selectedsuch that it is sufficient to yield a therapeutically effective dose.The amount of diuretic compound required to provide a therapeuticallyeffective dose is generally known in the art, and is discussed in moredetail below. The substrate area may then be determined using thefollowing equation: film thickness (cm) × drug density (g/cm3) ×substrate area (cm2) = dose (g) OR substrate area (cm2) = dose (g)/[filmthickness (cm) × drug density (g/cm3)]

[0075] The drug mass can be determined by weighing the substrate beforeand after formation of the drug film or by extracting the drug andmeasuring the amount analytically. Drug density can be determinedexperimentally by a variety of well known techniques, or may be found inthe literature or in reference texts, such as in the CRC. An assumptionof unit density is acceptable if an actual drug density is not known.

[0076] Dosage of Diuretic Containing Aerosols

[0077] The dose of a diuretic compound or compounds in aerosol form isgenerally no greater than twice the standard dose of the drug givenorally. For instance, ethacrynic acid, bumetanide, muzolimine,torsemide, or tripamide are given at strengths of 25 mg to 50 mg, 0.5 mgto 2 mg, 40 mg to 150 mg, 5 mg to 100 mg, and 5 mg to 15 mg respectivelyfor the treatment of edema. As aerosols, 10 mg to 100 mg of ethacrynicacid, 0.1 mg to 10 mg of bumetanide, 10 mg to 200 mg of muzolimine, 1 mgto 150 mg of torsemide, and 1 mg to 25 mg of tripamide are generallyprovided per inhalation for the same indication.

[0078] A dosage of a diuretic containing aerosol may be administered ina single inhalation or may be administered in more than one inhalation,such as a series of inhalations. Where the drug is administered as aseries of inhalations, the inhalations are typically taken within anhour or less (dosage equals sum of inhaled amounts). When the drug isadministered as a series of inhalations, a different amount may bedelivered in each inhalation.

[0079] One can determine the appropriate dose of a diuretic containingaerosol to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human and they typically provide accurateextrapolation of tests results to humans. Initial dose levels fortesting in humans are generally less than or equal to the dose in themamal model that resulted in plasma drug levels associated with atherapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered.

[0080] Particle Size

[0081] Efficient aerosol delivery to the lungs requires that theparticles have certain penetration and settling or diffusionalcharacteristics. Deposition in the deep lungs occurs by gravitationalsettling and requires particles to have an effective settling size,defined as mass median aerodynamic diameter (MMAD), typically between1-3.5 Am. Typically, in order to produce particles having a desiredMMAD, gas or air is passed over the solid support at a certain flowrate.

[0082] Typically, the higher the flow rate, the smaller the particlesthat are formed. Therefore, in order to achieve smaller or largerparticles, the flow rate through the condensation region of the deliverydevice may be altered. This may be done, for example, by modifying agas-flow control valve to increase or decrease the volumetric airflowrate. To illustrate, condensation particles in the size range 1-3.5 μmMMAD may be produced by selecting the gas-flow rate to be in a range of4-50 L/minute.

[0083] Additionally, as will be appreciated by one of skill in the art,particle size may also be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate. In addition, particle size may also bealtered by the presence or absence of structures that produce turbulencewithin the chamber. Thus, for example to produce condensation particlesin the size range 10-100 nm MMAD, the chamber may provide gas-flowbarriers for creating air turbulence within the condensation chamber.These barriers are typically placed within within a few thousands of aninch from the substrate surface.

[0084] Analysis of Diuretic Containing Aerosols

[0085] Purity of a diuretic containing aerosol may be determined using anumber of different methods. It should be noted that when the term“purity” is used, it refers to the percentage of aerosol minus thepercent byproduct produced in its formation. Byproducts for example, arethose unwanted products produced during vaporization. For example,byproducts include thermal degradation products as well as any unwantedmetabolites of the active compound or compounds. Examples of suitablemethods for determining aerosol purity are described in Sekine et al.,Journal of Forensic Science 32:1271-1280 (1987) and in Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989).

[0086] One suitable method involves the use of a trap. In this method,the aerosol is collected in a trap in order to determine the percent orfraction of byproduct. Any suitable trap may be used. Suitable trapsinclude filters, glass wool, impingers, solvent traps, cold traps, andthe like. Filters are often most desirable. The trap is then typicallyextracted with a solvent, e.g. acetonitrile, and the extract subjectedto analysis by any of a variety of analytical methods known in the art,for example, gas, liquid, and high performance liquid chromatographyparticularly useful.

[0087] The gas or liquid chromatography method typically includes adetector system, such as a mass spectrometry detector or an ultravioletabsorption detector. Ideally, the detector system allows determinationof the quantity of the components of the drug composition and of thebyproduct, by weight. This is achieved in practice by measuring thesignal obtained upon analysis of one or more known mass(es) ofcomponents of the drug composition or byproduct (standards) and thencomparing the signal obtained upon analysis of the aerosol to thatobtained upon analysis of the standard(s), an approach well known in theart.

[0088] In many cases, the structure of a byproduct may not be known or astandard for it may not be available. In such cases, one may calculatethe weight fraction of the byproduct by assuming it has an identicalresponse coefficient (e.g. for ultraviolet absorption detection,identical extinction coefficient) to the drug component or components inthe diuretic composition. When conducting such analysis, byproductspresent in less than a very small fraction of the drug compound, e.g.less than 0.2% or 0.1% or 0.03% of the drug compound, are typicallyexcluded. Because of the frequent necessity to assume an identicalresponse coefficient between drug and byproduct in calculating a weightpercentage of byproduct, it is often more desirable to use an analyticalapproach in which such an assumption has a high probability of validity.In this respect, high performance liquid chromatography with detectionby absorption of ultraviolet light at 225 nm is typically desirable. UVabsorption at 250 nm may be used for detection of compounds in caseswhere the compound absorbs more strongly at 250 nm or for other reasonsone skilled in the art would consider detection at 250 nm the mostappropriate means of estimating purity by weight using HPLC analysis. Incertain cases where analysis of the drug by UV are not viable, otheranalytical tools such as GC/MS or LC/MS may be used to determine purity.

[0089] It is possible that modifying the form of the drug may impact thepurity of the aerosol obtained. Although not always the case, the freebase or free acid form of the drug as opposed to the salt, generallyresults in either a higher purity or yield of the resultant aerosol.Therefore, in certain circumstances, it may be more desirable to use thefree base or free acid forms of the compounds used. Similarly, it ispossible that changing the gas under which vaporization of thecomposition occurs may also impact the purity.

[0090] Other Analytical Methods

[0091] Particle size distribution of a diuretic containing aerosol maybe determined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0092] Inhalable aerosol mass density may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0093] Inhalable aerosol drug mass density may be determined, forexample, by delivering a drug-containing aerosol into a confined chambervia an inhalation device and measuring the amount of active drugcompound collected in the chamber. Typically, the aerosol is drawn intothe chamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0094] Inhalable aerosol particle density may be determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device and measuring the number of particles of given sizecollected in the chamber. The number of particles of a given size may bedirectly measured based on the light-scattering properties of theparticles. Alternatively, the number of particles of a given size may bedetermined by measuring the mass of particles within the given sizerange and calculating the number of particles based on the mass asfollows: Total number of particles=Sum (from size range 1 to size rangeN) of number of particles in each size range. Number of particles in agiven size range=Mass in the size range/Mass of a typical particle inthe size range. Mass of a typical particle in a given size range=π*D³φ6,where D is a typical particle diameter in the size range (generally, themean boundary MMADs defining the size range) in microns, φ is theparticle density (in g/mL) and mass is given in units of picograms(g⁻¹²).

[0095] Rate of inhalable aerosol particle formation may be determined,for example, by delivering aerosol phase drug into a confined chambervia an inhalation device. The delivery is for a set period of time(e.g., 3 s), and the number of particles of a given size collected inthe chamber is determined as outlined above. The rate of particleformation is equal to the number of 100 nm to 5 micron particlescollected divided by the duration of the collection time.

[0096] Rate of aerosol formation may be determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0097] Rate of aerosol formation may be determined, for example, bydelivering a diuretic containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure diuretic, the amount of drug collected in the chamber ismeasured as described above. The rate of drug aerosol formation is equalto the amount of diuretic collected in the chamber divided by theduration of the collection time. Where the diuretic containing aerosolcomprises a pharmaceutically acceptable excipient, multiplying the rateof aerosol formation by the percentage of diuretic in the aerosolprovides the rate of drug aerosol formation.

[0098] Methods of Treating Edema

[0099] Also described herein are methods for treating edema. Typicallythe methods comprise the step of administering a therapeuticallyeffective amount of a diuretic condensation aerosol to a person withedema. Typically the step of administering the diuretic condensationaerosol comprises the step of administering an orally inhalable diureticcondensation aerosol to the person with edema.

[0100] The diuretic aerosol may be administered in a single inhalation,or in more than one inhalation, as described above. In some variations,the diuretic achieves a C_(max) in 10 minutes or less after the step ofadministering the aerosol. In other variations, the diuretic achieves aC_(max) in less than 5 minutes, less than 2 minutes, or less than 1minute after the step of administering the aerosol.

[0101] The edema may be associated, at least in part, with any number ofcauses or maladies. For example, the edema may be associated with acause selected from the group consisting of congestive heart failure,cirrhosis of the liver, poor blood circulation, lymphatic systemfailure, chronic nephritis, malnutrition, preeclampsia, use of birthcontrol pills, premenstrual syndrome, sunburn, hypertension, Meniere'sdisease, glaucoma, cystic fibrosis, and an imbalance of sodium andpotassium.

[0102] The diuretic condensation aerosol may comprise a diureticcomposition as described above. The diuretic composition typicallycomprises at least one diuretic selected from the group consisting ofbumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone,torsemide, triamterene, tripamide, BG 9928, and BG 9719. In somevariations, the diuretic is bumetanide. In some variations, the diureticcondensation

[0103] In some variations, the method for treating edema comprising thestep of administering a therapeutically effective amount of a diureticaerosol to a person with edema, wherein the diuretic aerosol comprises adiuretic compound and has a MMAD in the range of about 1-3 μm, andwherein a peak plasma level of at least 30 ng/mL of the diureticcompound is achieved within 10 minutes of administration. In somevariations, the method comprises the steps of obtaining a weightmeasurement of the person with edema prior to the step of administeringa therapeutically effective amount of a diuretic aerosol, and using thatweight measurement to assess whether to administer a therapeuticallyeffective amount of a diuretic aerosol.

[0104] Methods of Treating Congestive Heart Failure

[0105] Also described herein are methods for treating congestive heartfailure using loop diuretics such as bumetanide, torsemide, ethacrynicacid, and furosemide, for reasons unrelated or in addition to thetreatment of edema. Typically the methods comprise the step ofadministering a therapeutically effective amount of a loop diureticcondensation aerosol to a person with congestive heart failure.Typically the step of administering the diuretic condensation aerosolcomprises the step of administering an orally inhalable loop diureticcondensation aerosol to the person with congestive heart failure.

[0106] The loop diuretic aerosol may be administered in a singleinhalation, or in more than one inhalation, as described above. In somevariations, the loop diuretic achieves a C_(max) in 10 minutes or lessafter the step of administering the aerosol. In other variations, theloop diuretic achieves a C_(max) in less than 5 minutes, less than 2minutes, or less than 1 minute after the step of administering theaerosol.

[0107] In the treatment of congestive heart failure, the modulation ofthe vascular tone of arteries, arterioles, venuoles, and/or veins can beuseful. When delivered with an appropriate absorption pharmacokinetics,in particular the absorption pharmacokinetics produced by inhalationdelivery using the methods described herein, diuretics, in particularloop diuretics, may produce a useful relaxation of particular bloodvessels. Such relaxation or vasodilation serves to ameliorate thesymptoms of congestive heart failure. While such relaxation may beuseful at any point in the course of treatment of congestive heartfailure, it is of particular benefit in the treatment of congestiveheart failure exacerbations, where a patient experiences increasingsymptoms, generally including increasing shortness of breath. In suchcases, inhalation of a loop diuretic may result in almost immediateimprovement in such symptoms, even before substantial relief of edemaoccurs or in certain cases even unrelated to the treatment of edema.

[0108] The loop diuretic condensation aerosol may comprise a loopdiuretic composition as described above. The diuretic compositiontypically comprises at least one loop diuretic selected from the groupconsisting of bumetanide, ethacrynic acid, furosemide, and torsemide. Insome variations, the loop diuretic is bumetanide. In some variations,the loop diuretic condensation aerosol has a MMAD in the range of about1-3 μm.

[0109] In some variations, the method for treating congestive heartfailure comprising the step of administering a therapeutically effectiveamount of a loop diuretic aerosol to a person with congestive heartfailure, wherein the loop diuretic aerosol comprises a loop diureticcompound and has a MMAD in the range of about 1-3 μm, and wherein a peakplasma level of at least 30 ng/mL of the loop diuretic compound isachieved within 10 minutes of administration.

[0110] Working Examples

[0111] The following working examples are meant to be illustrative, andare in no way intended to limit the scope of the invention. Ethacrynicacid and bumetanide are commercially available from Sigma-Aldrich(www.sigma-aldrich.com).

EXAMPLE 1A Volatilization of Ethacrynic Acid

[0112] About 1.1 mg of ethacrynic acid (MW 303, melting point 122° C.,oral dose 25 mg) was dip coated onto the stainless steel surface of aflashbar apparatus at a thickness of about 1.32 μm. (The flashbar is acylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollow tubeof 0.005″ thick stainless steel.) Brass electrodes were connected toeither end of the steel cylinder. The coated flashbar was secured in anelectrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporizaton chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis indicated that the aerosol was 99.83%ethacrynic acid.

[0113] To obtain higher purity aerosols, one can coat a lesser amount ofdrug, yielding a thinner film to heat. A linear decrease in filmthickness is associated with a linear decrease in impurities.

EXAMPLE 1B Volatilization of Ethacrynic Acid

[0114] About 1.01 mg of ethacrynic acid (MW 303, melting point 122° C.,oral dose 25 mg) was dip coated onto the stainless steel surface of aflashbar apparatus at a thickness of about 1.21 μm. (The flashbar is acylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollow tubeof 0.005″ thick stainless steel.) Brass electrodes were connected toeither end of the steel cylinder. The coated flashbar was secured in anelectrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporization chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis indicated that the aerosol was 99.57%ethacrynic acid.

EXAMPLE 2 Volatilization of Bumetanide

[0115] About 1.09 mg of bumetanide (MW 364, melting point 231° C., oraldose 0.5 mg) was dip coated onto the stainless steel surface of aflashbar apparatus at a thickness of about 1.3 μm. (The flashbar is acylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollow tubeof 0.005″ thick stainless steel.) Brass electrodes were connected toeither end of the steel cylinder. The coated flashbar was secured in anelectrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporization chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis indicated that the aerosol was 98.44%bumetanide.

[0116] High speed photographs were taken as the drug-coated substratewas heated to monitor visually formation of a thermal vapor. Thephotographs showed that a thermal vapor was initially visible 40milliseconds after heating was initiated, with the majority of thethermal vapor formed by 300 milliseconds. Generation of the thermalvapor was complete by 1200 milliseconds.

EXAMPLE 3A Volatilization of Spironolactone

[0117] About 0.71 mg of spironolactone (MW 417, melting point 135° C.,oral dose 25 mg) was dip coated onto the stainless steel surface of aflashbar apparatus at a thickness of about 0.85 μm. (The flashbar is acylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollow tubeof 0.005″ thick stainless steel.) Brass electrodes were connected toeither end of the steel cylinder. The coated flashbar was secured in anelectrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporization chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis is indicated that the aerosol was 100%spironolactone.

EXAMPLE 3B Volatilization of Spironolactone

[0118] About 0.84 mg of spironolactone (MW 417, melting point 135° C.,oral dose 25 mg) was dip coated onto the stainless steel surface of aflashbar apparatus at a thickness of about 1.01 μm. (The flashbar is acylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollow tubeof 0.005″ thick stainless steel.) Brass electrodes were connected toeither end of the steel cylinder. The coated flashbar was secured in anelectrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporization chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis indicated that the aerosol was 100%spironolactone.

EXAMPLE 4A Volatilization of Triamterene

[0119] About 0.733 mg of triamterene (MW 253, melting point 316° C.,oral dose 100 mg) was dissolved in 50 μl of 88% formic acid and drippedonto the stainless steel surface of a flashbar apparatus at a thicknessof about 0.97 μm. (The flashbar is a cylinder 3.5 cm long and 1.3 cm indiameter consisting of a hollow tube of 0.005″ thick stainless steel.)Brass electrodes were connected to either end of the steel cylinder. Thecoated flashbar was secured in an electrical mount, which connected totwo 1.0 Farad capacitors in parallel. An airway was provided by a 2 cmdiameter glass sleeve placed around the flashbar. 15 L/min of room airwere pulled by a house vacuum through the vaporization chamber and afilter housing, which contained a two-micron Teflon filter. A powersupply charged the capacitors to 20.5 volts, at which point the circuitwas closed with a switch and the stainless steel flashbar wasresistively heated to about 400° C. within about 200 milliseconds. Thedrug aerosolized and flowed through the airway and into the filter. TheTeflon filter was extracted with 5 Ml of acetonitrile, and the samplewas run through an HPLC for purity analysis. Purity analysis indicatedthat the aerosol was 99.76% triamterene.

EXAMPLE 4B Volatilization of Triamterene

[0120] About 0.841 mg of triamterene (MW 253, melting point 316° C.,oral dose 100 mg) was manually coated onto the stainless steel surfaceof a flashbar apparatus at a thickness of about 1.11 μm. (The flashbaris a cylinder 3.5 cm long and 1.3 cm in diameter consisting of a hollowtube of 0.005″ thick stainless steel.) Brass electrodes were connectedto either end of the steel cylinder. The coated flashbar was secured inan electrical mount, which connected to two 1.0 Farad capacitors inparallel. An airway was provided by a 2 cm diameter glass sleeve placedaround the flashbar. 15 L/min of room air were pulled by a house vacuumthrough the vaporization chamber and a filter housing, which contained atwo-micron Teflon filter. A power supply charged the capacitors to 20.5volts, at which point the circuit was closed with a switch and thestainless steel flashbar was resistively heated to about 400° C. withinabout 200 milliseconds. The drug aerosolized and flowed through theairway and into the filter. The Teflon filter was extracted with 5 mL ofacetonitrile, and the sample was run through an HPLC for purityanalysis. Purity analysis indicated that the aerosol was 100%triamterene.

PROPHETIC EXAMPLES

[0121] The following prophetic examples are meant to be illustrative,and are in no way intended to limit the scope of the invention. As notedabove, bumetanide is commercially available from Sigma-Aldrich(www.sigma-aldrich.com).

EXAMPLE 5 Inhalation Toxicology and Pharmacokinetic Study of InhaledAerosol Formulations of Bumetanide in the Beagle Dog.

[0122] This example is meant to illustrate one way in which toxicologyand pharmacokinetic data may be investigated with respect to thebumetanide condensation aerosols described herein. Toxicology andpharmacokinetic data may be gathered by studying daily oropharyngealinhalation of bumetanide condensation aerosols over a 14 day periodusing a beagle dog model.

[0123] Beagle dogs are purchased from Covance Research Product, Route 2,Box 113, Cumberland, Va. 23040 and are approximately 7-10 months of ageand 6-12 kg at the onset of treatment. They are housed individually instainless steel cages equipped with a bar-type floor and an automaticwatering valve. Each cage is clearly labeled with a color-coded cagecard indicating project, group, animal and tattoo number and sex. Eachanimal is uniquely identified by a permanent tattoo number and/or letteron the ventral aspect of one pinna.

[0124] All animals have access to a standard certified pelletedcommercial dog food (400 g—PMI Certified Dog Chow 5007: PMI NutritionInternational Inc.) except during designated procedures. Municipal tapwater which is softened, purified by reverse osmosis and exposed toultraviolet light is freely available except during designatedprocedures. An acclimation period of approximately 3 weeks is allowedbetween animal receipt and the start of treatment in order to accustomthe animals to the laboratory environment.

[0125] Before treatment initiation, all animals are weighed and assignedto treatment groups using a randomization procedure. Animals areassigned into the following groups: bumetanide high dose, bumetanide middose, bumetanide low dose, and vehicle control at 3 animals per sex perdose. The dose levels for bumetanide are generally approximately 0.1mg/kg for the low dose group, 0.5 mg/kg for the mid dose group, and 2mg/kg for the high dose group. The dose levels can be refined through aninitial dose ranging toxicology study.

[0126] Animals are treated with the test aerosols using an oropharyngealface mask fitted with inlet and outlet tubes. During treatment, animalsare placed in a restraint sling. A mask that allows the inhalation oftest material to dogs is used. The test article is generated byvaporizing bumetanide by heating to roughly 400° C. The bumetanide is anapproximately 1 micron thick film coating on a stainless steel foil,which was deposited on the foil by dip coating the foil into a solutionof bumetanide dissolved in organic solvent.

[0127] The resulting aerosol formed by the condensation of the vaporizedbumetanide is introduced into a mixing chamber via pre-dried compressedair. The mixing chamber is operated under slight positive pressuremaintained by means of a gate valve located in the exhaust line. Avacuum pump is used to exhaust the inhalation chamber at the requiredflow rate and draw the contaminated air (excess aerosol and expired air)through a purifying system consisting of a 5 μm coarse filter beforeexpelling the air from the building. The resulting atmosphere is carriedto the dog mask via a delivery tube.

[0128] The vehicle control group is exposed to predried compressed airpassed through the drug-heating apparatus with the apparatus loaded witha clean stainless steel foil instead of a bumetanide-coated foil. Exceptfor absence of drug, exposure is matched to the high dose bumetanidegroup, in terms of the air being passed through the operating and thusheating apparatus and the dogs breathing only through the dog masks, andthe dogs being restrained and handled in the same manner.

[0129] To ensure that the doses are correct, prior to the start of thetreatment each day, atmosphere characterization of the test articleaerosol is performed. Analysis of the aerosol particle size distributionfor each bumetanide dose is conducted using a Cascade Impactor. Typicalmass median aerodynamic diameter and geometric standard deviationmeasured during the study are 1.5 μm±2. Actual mask outputconcentrations of aerosol are measured during each exposure day from asampling port from the animal breathing zone.

[0130] The achieved dose of active ingredient (mg/kg/day) for eachtreatment level is determined as follows:

Achieved Dose of Active Ingredient=[RMV×Active Concentration×T×D]/BW

[0131] Where the achieved dose of the active ingredient is in mg/kg/day;the RMV (i.e., respiratory minute volume) is in L/min; the ActiveConcentration (i.e., chamber concentration of active ingredientdetermined by chemical analysis) is in mg/L; T (i.e., treatment time) isin minutes; D is the total aerosol deposition fraction, according to theparticle size; and BW (i.e., mean body weight per sex per group from theregular body weight occasions during treatment) is in kg.

[0132] Dogs are treated with the bumetanide aerosol using the aboveapproach to deliver the drug aerosol and compute the delivered dose. Theexposure period required to deliver a dose is typically approximately 10minutes. Plasma samples for pharmacokinetic analysis are collected onone or more treatment days. Samples are typically collected pre-dose, 2minutes into dosing, and the end of dosing, 20 minutes post dose, 1 hourpost dose, 3 hours post dose, 9 hours post dose, and 24 hours post dose.Samples are analyzed by an appropriate method such as LC/MS or LC/MS/MSto determine the pharmacokinetics of bumetanide absorption andelimination.

[0133] Treatment results in rapid increases in bumetanide peak plasmalevels, which occur at the end of treatment (i.e., generally within 10minutes, assuming a treatment duration of 10 minutes or less).Substantial drug blood levels are already obtained at the 2 minute timepoint. Peak plasma blood levels of bumetanide exceed 30 ng/mL in the lowdose group, 100 ng/mL in the mid dose group, and 300 ng/mL in the highdose group. Plasma levels at two minutes exceed 10 ng/mL in the low dosegroup, 30 ng/mL in the mid dose group, and 100 ng/mL in the high dosegroup. Immediately following drug administration, an increase inurination is noted, which persists for an approximately 4 hour periodfollowing treatment. Food consumption is roughly normal in all animals,with the possible exception of the high dose bumetanide group.

[0134] Animals are necropsied on completion of the treatment period. Inorder to avoid autolytic change, a complete gross pathology examinationof the carcass is conducted immediately on all animals. No treatmentrelated findings are detected during necropsy for any of the animals.Histopathological examination of any gross lesions is conducted. Again,no treatment related findings are observed. In addition,histopathological examination of the larynx, trachea, mainstem bronchi,lungs including bronchi are conducted. No treatment relatedabnormalities are observed, with the possible exception of minor changesin airway, nose, or lung histology in the high dose group.

EXAMPLE 6 Delivery of a Single Bolus Inhalation of BumetanideCondensation Aerosol to Anesthetized and Intubated Beagle Dog.

[0135] A condensation aerosol generating apparatus consisting of a heatsource and a bumetanide coated solid support is assembled. Thebumetanide solid support has a surface area of approximately 10 cm² andan approximately 1 μm thick film of bumetanide aerosol of approximately1 mg. The heat source is capable of heating to at least 250° C., but notgreater than 500° C. The assembly is capable of being initiated togenerate condensation aerosol upon input of an electrical signal.

[0136] Three beagle dogs are catheterized in their femoral vein. Thenthe dogs receive a pre-anesthetic dose of acepromazine (0.2 mL),followed by anesthesia with 5% isoflurane about 15 minutes later. Anendotracheal tube is positioned in the trachea, the cuff inflated andanesthesia maintained using 2% isoflurane in oxygen. Dogs are thenplaced into a holding sling and connected to a condensation aerosolgenerator by the endotracheal tube. A monitoring system is used tomeasure the inspiration and expiration of the dogs, which is controlledby mechanical ventilation.

[0137] The test animals are induced into a state of apnea using positivepressure hyperventilation to prevent spontaneous breathing frominterrupting the aerosol delivery. The monitoring system is used to timeaerosol generation so that it occurs in the first portion of theventilator-controlled inhalation phase of breathing. The aerosoldelivery breath is preceded by ventilator-controlled near completeexhalation. A large tidal volume (generally not exceeding 1 L, to avoidthe risk of pneumothorax) is then used for the aerosol delivery breath,followed by a 3 s breath-hold to maximize alveolar delivery. Such abreathing pattern mimics that of a patient instructed to “exhale, andthen take a deep breath.” Patients are familiar with breathing in thispattern when having their lungs examined by a doctor using astethoscope. The condensation aerosol generating device connected to theendotracheal tube is activated near the beginning of the aerosoldelivery breath, delivering the condensation aerosol over approximatelythe first second or less of that breath.

[0138] Venous blood samples are obtained at 0.3, 1, 3, 10, 30, 60, 120,240, and 480 minutes after dosing. Plasma drug concentrations aredetermined using established methods described in the literature forbumetanide. These analyses reveal a T_(max) of less than 10 minutes,with the T_(max) generally occurring at the 3 minute sample or the 1minute sample. C_(max) is greater than 30 ng/mL, typically greater than100 ng/mL, and often approximately 500 ng/mL. Bioavailability of thecondensation aerosol delivery is greater than 50% of intravenousdelivery, and often greater than 75% of intravenous delivery.

EXAMPLE 7 Phase I/II Clinical Trial of Bumetanide Condensation Aerosol.

[0139] A condensation aerosol generating handheld device asillustratively described above, is coated with bumetanide so as torelease a 0, 0.25, 0.5, 1, or 2 mg (depending on coating thickness) ofbumetanide condensation aerosol over a period of less than 1 secondfollowing actuation of the device by patient inspiration.

[0140] For the Phase I clinical trial, normal volunteers generally inthe 18 to 45 year age range and not suffering from serious pulmonary,renal or cardiovascular disease are recruited to participate in thestudy, explained the potential risks of bumetanide inhalation, and askedfor their informed consent. Those consenting are enrolled in the study.For a Phase I/II or Phase II study, the normal volunteers are replacedby patients with edema. Such patients are likely to have seriouscardiovascular or renal disease. Except for this difference, the patientvolunteers are consented, enrolled, and treated similar to the normalvolunteers, except additional safety monitoring may be required.

[0141] An intravenous catheter is placed. In addition, a foley cathetermay be placed to enable minute by minute measurement of urine output.Urine output is generally monitored for a period of at least 2 hoursprior to dosing.

[0142] Volunteers are then given a handheld device. They may or may notbe trained in appropriate breathing technique for use of the deviceprior to receiving the device. Minimally, each volunteer is instructedto exhale fully, then place the device in his or her lips and take along, deep inhalation which is held for several seconds prior toexhaling. The volunteer then uses the device, receiving the prescribedquantity of bumetanide condensation aerosol. The volunteer and themedical personnel coriducting the study may be blinded as to the dose ofdrug, or as to whether the drug is replaced by placebo (i.e., a deviceloaded with 0 mg bumetanide).

[0143] Venous blood samples are obtained approximately at 0.3, 1, 3, 10,30, 60, 120, 240, 360, 500, 750, and 1000 minutes after dosing. Plasmadrug concentrations are determined using established methods describedin the literature for bumetanide. These analyses reveal a T_(max) ofless than 10 minutes, with the T_(max) generally occurring at the 3minute sample or the 1 minute sample. Bioavailability of thecondensation aerosol delivery is greater than 35% of intravenousdelivery, and often greater than 55% of intravenous

[0144] The below table provides illustrative anticipated C_(max) valuesat different doses: Dose C_(max) typically greater than Most typicalC_(max) greater than 0.25 mg 2.7 ng/mL  25 ng/mL  0.5 mg   5 ng/mL  50ng/mL   1 mg  10 ng/mL 100 ng/mL   2 mg  20 ng/mL 200 ng/mL

[0145] After inhalation of the condensation aerosol, an increase inurine output is noted almost immediately. For patients treated with 1 mgor 2 mg of bumetanide and having a foley catheter in place, an increasein urine output is frequently detectable with 10 minutes, or at most 20minutes of condensation aerosol inhalation. For patients receiving lowerdoses or not having a foley catheter in place, increases in urine outputalso occur almost immediately but may be more difficult to detect.

EXAMPLE 8 Determination of Whether Aerosol Delivery of Loop Diuretic isTherapeutically Indicated by Patient Self-Weighing at Home.

[0146] A female patient of 70 years with a history of congestive heartfailure (e.g., New York Heart Association grade III), is instructed toweigh herself on a daily basis. Records of the patient's weight revealthat, when the patient feels relatively good, her weight is within 1 kgof her 80 kg base weight upon weighing in the morning prior to eating.Records further reveal that a weight gain of over 1 kg to greater than81 kg is associated with increased symptoms of difficulty in walking.Yet further weight gain is associated with shortness of breath at rest.The patient is instructed to call her medical provider whenever shemeasures her weight (on an empty stomach) at above 81 kg. The medicalprovider reviews the patient's history and symptoms by telephone,focusing on recent diet (e.g., increased salt intake), symptoms ofedema, difficulty breathing, and any symptoms of more serious illness.If the patient seems to be acutely decompensating due to edema, thepatient is instructed to take a 2 mg dose of the bumetanide aerosol andimmediately seek medical aid. If the patient seems to have a minorincrease in edema, she is instructed to take a 1 mg dose of thebumetanide aerosol.

EXAMPLE 9 Determination of Whether Aerosol Delivery of Loop Diuretic isTherapeutically Indicated by Weighing of Patient in a Medical Office.

[0147] A male patient of 52 years with a history of congestive heartfailure (e.g., New York Heart Association grade IV), experiencesincreasing shortness of breath at rest and decides to seek medicalassistance. Upon reaching his doctor's office, the patient's vital signsare measured and found to be normal except for mild tachypnea. There isno fever. The patient is weighed and his weight compared to last visit,which was a routine visit not during a congestive heart failureexacerbation. His weight has increased by 3 kg. The patient is given acondensation aerosol dose of 1 mg bumetanide. Within 30 minutes,shortness of breath improves and the patient is able to go home.

EXAMPLE 10 Clinical Trial of the Efficacy of Bumetanide CondensationAerosol in Congestive Heart Failure Exacerbations.

[0148] A condensation aerosol generating handheld device asillustratively described above, is coated with bumetanide so as torelease a 0, 0.5, 1, or 2 mg (depending on coating thickness) ofbumetanide condensation aerosol over a period of less than 1 secondfollowing actuation of the device by patient inspiration.

[0149] For the clinical trial, patients presenting to the emergencydepartment with a history of congestive heart failure of New York HeartAssociation grade II or above with symptoms of a congestive heartfailure exacerbation including a subjective sensation of shortness ofbreath, increased respiratory rate (>20 per minute) and/or poor oxygensaturation (<95%) when breathing room air, but not in such severedistress as to require immediate treatment, are recruited to participatein the study, explained the potential risks of bumetanide inhalation,and asked for their informed consent. Those consenting are enrolled inthe study and randomized to receive a particular bumetanide dose.

[0150] Patients are then given a handheld device. They may or may not betrained in appropriate breathing technique for use of the device priorto receiving the device. Minimally, each patient is instructed to exhalefully, then place the device in his or her lips and take a long, deepinhalation which is held for several seconds prior to exhaling. Thepatient then uses the device, receiving the prescribed quantity ofbumetanide condensation aerosol. The patient and the medical personnelconducting the study are blinded as to the dose of drug, or as towhether the drug is replaced by placebo (i.e., a device loaded with 0 mgbumetanide).

[0151] After inhalation of the condensation aerosol, an improvement inthe congestive heart failure exacerbation is noted almost immediately,in general at a similar time as the first onset of diuretic effect butpreceding clinically relevant diuresis. Inhalation of the condensationaerosol results in a clinically relevant reduction in shortness ofbreath and associated respiratory measures such as oxygen saturationwhen breathing room air and respiratory rate, compared to inhalation ofplacebo. Assuming enrollment of a sufficient patient sample,statistically significant effects at the p<0.05 level are obtained forinhaled drug vs. inhaled placebo within 20 minutes or less afterinhalation.

[0152] While the present invention has been described with reference toone or more particular variations, those skilled in the art willrecognize that many changes may be made hereto without departing fromthe spirit and scope of the devices and methods herein described andclaimed.

What we claim is:
 1. A method for treating edema comprising the step of:administering a therapeutically effective amount of a diureticcondensation aerosol to a person with edema, wherein the step ofadministering comprises the step of administering an orally inhalablediuretic condensation aerosol to the person with edema.
 2. The method ofclaim 1 wherein the edema is associated at least in part, with a causeselected from the group consisting of congestive heart failure,cirrhosis of the liver, poor blood circulation, lymphatic systemfailure, chronic nephritis, malnutrition, preeclampsia, use of birthcontrol pills, premenstrual syndrome, sunburn, hypertension, Meniere'sdisease, glaucoma, cystic fibrosis, and an imbalance of sodium andpotassium.
 3. The method of claim 1 wherein the diuretic condensationaerosol comprises a diuretic selected from the group consisting ofbumetanide, ethacrynic acid, muzolimine, spironolactone, triamterene,tripamide, BG 9928, and BG
 9719. 4. The method of claim 3 wherein thediuretic is bumetanide.
 5. The method of claim 1 wherein the diureticcondensation aerosol has a MMAD in the range of about 1-3 μm.
 6. Themethod of claim 1 wherein the diuretic achieves a C_(max) in 10 minutesor less after the step of administering the aerosol.
 7. The method ofclaim 1 wherein the step of administering the diuretic condensationaerosol comprises the step of administering the diuretic condensationaerosol in a single inhalation.
 8. The method of claim 1 wherein thestep of administering the diuretic condensation aerosol comprises thestep of administering the diuretic condensation aerosol in more than oneinhalation.
 9. A method for forming a diuretic condensation aerosolcomprising the steps of: providing a diuretic composition; andvaporizing the diuretic composition, wherein the step of vaporizing thediuretic composition comprises the step of heating the composition toform a vapor.
 10. The method of claim 9 wherein the diuretic compositioncomprises a diuretic selected from the group consisting of bumetanide,ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide,triamterene, tripamide, BG 9928, and BG
 9719. 11. The diureticcondensation aerosol of claim 10 wherein the diuretic is bumetanide. 12.The method of claim 9 wherein the diuretic composition further comprisesa pharmaceutically acceptable excipient.
 13. A diuretic condensationaerosol comprising: diuretic condensation aerosol particles, wherein thecondensation aerosol particles comprise a diuretic selected from thegroup consisting of bumetanide, ethacrynic acid, muzolimine,spironolactone, triamterene, tripamide, BG 9928, and BG 9719 and whereinthe diuretic condensation aerosol has a MMAD in the range of about 1-3μm.
 14. The diuretic condensation aerosol of claim 13 wherein thediuretic is bumetanide.
 15. The diuretic condensation aerosol of claim13 wherein the aerosol comprises at least 50% by weight of diureticcondensation particles.
 16. The diuretic condensation aerosol of claim13 wherein the aerosol is substantially free of thermal degradationproducts.
 17. A kit for delivering a diuretic condensation aerosolcomprising: a composition comprising a diuretic compound in a unit doseform; and a device for forming a diuretic aerosol, wherein the devicefor forming a diuretic aerosol comprises an element configured to heatthe composition to form a vapor, an element allowing the vapor tocondense to form a condensation aerosol, and an element permitting auser to inhale the condensation aerosol.
 18. The kit of claim 17 whereinthe composition further comprises a pharmaceutically acceptableexcipient.
 19. The kit of claim 17 wherein the diuretic compound isselected from the group consisting of bumetanide, ethacrynic acid,furosemide, muzolimine, spironolactone, torsemide, triamterene,tripamide, BG 9928, and BG
 9719. 20. The kit of claim 19 wherein thediuretic is bumetanide.
 21. A method for treating edema comprising thestep of: administering a therapeutically effective amount of a diureticaerosol to a person with edema, wherein the diuretic aerosol comprises adiuretic compound and has a MMAD in the range of about 1-3 μm, andwherein a peak plasma level of at least 30 ng/mL of the diureticcompound is achieved within 10 minutes of administration, and whereinthe step of administering comprises the step of administering an orallyinhalable diuretic aerosol to the person with edema.
 22. The method ofclaim 21 wherein the diuretic compound is a loop diuretic.
 23. Themethod of claim 22 wherein the diuretic compound is bumetanide.
 24. Themethod of claim 21 wherein the edema is associated, at least in part,with congestive heart failure.
 25. The method of claim 21 furthercomprising the steps of: obtaining a weight measurement of the personwith edema prior to the step of administering a therapeuticallyeffective amount of a diuretic aerosol; and using the weight measurementto assess whether to administer a therapeutically effective amount of adiuretic aerosol.
 26. A method for treating congestive heart failureexacerbation comprising the step of: administering a therapeuticallyeffective amount of a loop diuretic condensation aerosol to a personwith congestive heart failure exacerbation, wherein the step ofadministering comprises the step of administering an orally inhalablediuretic condensation aerosol to the person with congestive heartfailure exacerbation.
 27. The method of claim 26, wherein the loopdiuretic condensation aerosol comprises a loop diuretic selected fromthe group consisting of bumetanide, ethacrynic acid, torsemide, andfurosemide.
 28. The method of claim 26, wherein the loop diureticcondensation aerosol has a MMAD in the range of about 1-3 μm.
 29. Themethod of claim 26 wherein the loop diuretic achieves a C_(max) in 10minutes or less after the step of administering the aerosol.
 30. Themethod of claim 26 wherein the step of administering the loop diureticcondensation aerosol comprises the step of administering the loopdiuretic condensation aerosol in a single inhalation.
 31. The method ofclaim 26 wherein the step of administering the diuretic condensationaerosol comprises the step of administering the diuretic condensationaerosol in more than one inhalation.